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SEPARATION OF ENANTIOMERS OF RACEMIC MIXTURE DONE BY CHIRAL SYNTHESIS OF MANNICH BASES... Article · August 2013 CITATIONS

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Nadim M. R. Chhipa et al. / International Journal of Advances in Pharmaceutical Research

IJAPR

Research Paper ISSN: 2230 – 7583

Available Online through www.ijapronline.org

SEPARATION OF ENANTIOMERS OF RACEMIC MIXTURE DONE BY CHIRAL SYNTHESIS OF MANNICH BASES HAVING VARIABLE ELECTRONEGATIVE ATOMS: O/S/NH Nadim M. R. Chhipa* and Dr. Dhrubo Jyoti Sen Postgraduate Research Laboratory, Department of Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Gujarat Technological University, Arvind Baug, Mehsana-384001, Gujarat, India E-mail: [email protected] Received on 18 – 05 - 2013

Revised on 26 – 05- 2013

Accepted on 27– 07 – 2013

ABSTRACT The enantiomers produced by the chiral synthesis of Mannich bases of 4-hydroxy benzaldehyde with urea/thiourea/guanidine and piperidine/morpholine produced 3+3 sets of total 6 pairs of enantiomers having one chiral carbon. All the 6 derivatives are isoster of piperidine and morpholine in which CH2 (methylene) of piperidine is isoster of O (oxygen) of morpholine. The compounds are acidic in nature due to the presence of phenolic group (OH) so brucine has been used as a separator moiety to resolute the d and l isomers produce in racemic mixture.). All the compounds have been characterized by UV, IR and specific rotation and TLC. Log P values of the compounds are found as follows due to the presence of variable electronegativity of O for urea (3.44), S for thiourea (2.58) and NH for guanidine (3.04+2.20=5.24): SCompound-4>Compound-6 (min) Compound-2: piperidine+thiourea, Compound-1: piperidine+urea, Compound-3: piperidine+guanidine, Compound-5: morpholine+thiourea, Compound-4: morpholine+urea, Compound-6: morpholine+guanidine Fantastic results show that piperidine (CH 2) moiety linked with thiourea/urea/guanidine is isosteres has higher logP than morpholine (O) because the CH 2 group is isosteres with O but the CH2 group is much more non polar than O so the logP values of piperidine moiety is higher than morpholine series. Specific rotation of the synthesised compounds showed remarkable similarity in piperidine/morpholine in thiourea, piperidine/morpholine in urea, piperidine/morpholine in guanidine series. Rf values of all the racemic mixtures and enantiomers separated by brucine has been observed. Separated isomers showed as Rf(1) is lower than Rf(2) in brucine. Key Words: Mannich bases, electronegativity, log P, piperidine, morpholine, brucine, urea, thiourea, guanidine, 4hydroxy benzaldehyde, chiral carbon, isoster, specific rotation, TLC. INTRODUCTION The main objective of this project is to synthesize racemic mixtures by chiral synthesis of Mannich bases having variable electronegative atoms: O/S/NH by using 4-hydoxybenzaldehyde with urea/thiourea/guanidine with piperidine/morpholine to produce 3+3=6 sets of compounds. Log P of all the compounds have been calculated and correlated with the electronegativity of the variable atoms oxygen/sulphur/nitrogen.1-5

X HN HN

NH2

* N

O HO

X

X

+ H2N HO

*= Chiral carbon NH2

HN

NH2

X=O/S/NH HN

* N O

O HO

Scheme

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NH

X HN

HN

*=Chiral carbon

NH2

X=O/S/NH *

N

NH2

*

N

Y=CH2/O HO

Y HO

1-[(4-hydroxyphenyl)(piperidin-1-yl)methyl]guanidine

Molecular Skeleton Molecular structure of synthesised compounds O HN

NH2

* N

logP= 0.65 Compound-3

HO 1-[(4-hydroxyphenyl)(piperidin-1-yl)methyl]urea

O HN *

NH2 N

O HO 1-[(4-hydroxyphenyl)(morpholin-4-yl)methyl]urea

logP= 1.10 Compound-1 S HN

logP= -0.14 Compound-4

NH2

S

*

N HN

HO 1-[(4-hydroxyphenyl)(piperidin-1-yl)methyl]thiourea

*

NH2 N O

HO 1-[(4-hydroxyphenyl)(morpholin-4-yl)methyl]thiourea

logP= 1.43 Compound-2 logP= 0.19 Compound-5

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Nadim M. R. Chhipa et al. / International Journal of Advances in Pharmaceutical Research NH HN *

Compound-6 NH2

N

O HO 1-[(4-hydroxyphenyl)(morpholin-4-yl)methyl]guanidine

MATERIALS AND METHODS 4-hydroxy benzaldehyde has been reacted with urea/thiourea/guanidine solution and piperidine/morpholine in 1mole ratio and heated on water bath with stirring until all the matters reacted to produce single spot in TLC and negative test for free aldehyde. Finally the product has been obtained by acidification of the reaction medium by HCl. The obtained product has been filtered and dried and recrystallized from aqueous ethanol.6-14

logP= -0.59

Sr. No. 1 2 3 4 5 6

Compound

Table-1, Physicochemical Parameters M.P. (ºC) Solubility

Specific rotation +2.20

LogP

Rf

1-[(4-hydroxyphenyl)(piperidin-1110ºC Methanol & 1.10 yl)methyl]urea Hot Water 1-[(4-hydroxyphenyl)(piperidin-198ºC Methanol & +2.90 1.43 (max) yl)methyl]thiourea Hot Water 1-[(4-hydroxyphenyl)(piperidin-190ºC Methanol & +3.30 0.65 yl)methyl]guanidine Hot Water 1-[(4-hydroxyphenyl)(morpholin-4118ºC Methanol & +2.30 -0.14 yl)methyl]urea Hot Water 1-[(4-hydroxyphenyl)(morpholin-4120ºC Methanol & +2.80 0.19 yl)methyl]thiourea Hot Water 1-[(4-hydroxyphenyl)(morpholin-4114ºC Methanol & +3.90 -0.59 (min) yl)methyl]guanidine Hot Water (max) Compound-2>Compound-1>Compound-3>Compound-5>Compound-4>Compound-6 (min)

0.57 0.32 0.42 0.42 0.36 0.46

Histogram of logP

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Spectral datas of the compounds UV Data: Sr. No. Compound 1 1-[(4-hydroxyphenyl)(piperidin-1-yl)methyl]urea 2 1-[(4-hydroxyphenyl)(piperidin-1-yl)methyl]thiourea 3 1-[(4-hydroxyphenyl)(piperidin-1-yl)methyl]guanidine 4 1-[(4-hydroxyphenyl)(morpholin-4-yl)methyl]urea 5 1-[(4-hydroxyphenyl)(morpholin-4-yl)methyl]thiourea 6 1-[(4-hydroxyphenyl)(morpholin-4-yl)methyl]guanidine

λmax(nm) 284 284 283 283 283 283

R2 0.990 0.994 0.994 0.985 0.981 0.999

IR Data: Compound 1: 1-[(4-hydroxyphenyl)(piperidin-1-yl)methyl]urea (KBr, cm-1): 3940.30, 3139.90 (Phenolic –OH), 3150-2700 (-C-H stretching), 2461.00-2887.21 (Amine Salts), 1240.27 (-C-O), 1947.97, 1861.18 (-C6H5), 1450.37, 1413.72 (-C-H bending), 821.62,862 (-C6H5, para), Aromatic out of plane bending observed at 954-696 (-C6H5). Compound 2: 1-[(4-hydroxyphenyl)(piperidin-1-yl)methyl]thiourea (KBr, cm-1): 3568.43, 2829.68 (Phenolic –OH), 3150-2700 (C-H stretching), 1600-1303 (-C-C), 1500 (-C=C), 1670 (-C=N), 1300-1000 (-C-N), 1909.59 (-N-C=S), stretching) 821.62, 877.55 (-C6H5, para), 950.700 (-C6H5, bending). Compound 3: 1-[(4-hydroxyphenyl)(piperidin-1-yl)methyl]guanidine (KBr, cm-1): 3967.71-2972.10 (Phenolic –OH, stretching), 2883.41-2461.11 (Amine salt), 3186.18 (-C6H5, stretching), 1589.40-1541.17 (-N-H bending), 1392.65-1018.45 (-C-N) and (-C-O), 954-702.11 (-C6H5, bending). Compound 4: 1-[(4-hydroxyphenyl)(morpholin-4-yl)methyl]urea (KBr, cm-1): 3299.98-2972.10 (Phenolic –OH), 3100-2700 (-C-H, stretching), 2788.88-2563.22 (Amine salts), 1163.00-1112.12 (-C-O), 1450.37, 1413.72 (-C-H, bending), 860.00-703.00 (-C6H5, bending). Compound 5: 1-[(4-hydroxyphenyl)(morpholin-4-yl)methyl]thiourea (KBr, cm-1): 3303.83-2752.23 (Phenolic –OH), 3100-2700 (-C-H, stretching), 1591.16 (-C-C), 1200-1100 (-C-N), 2356.85-2337.56 (-S-H), 1159.14 (-C-O). Compound 6: 1-[(4-hydroxyphenyl)(morpholin-4-yl)methyl]guanidine (KBr, cm-1): 3967.71-2827.45 (Phenolic –OH, stretching), 3186.18 (-C6H5, stretching), 1666.00 (-C=C), 1390.581163.00(-C-N) and (-C-O), 831-642.00 (-C6H5, bending).

Brucine

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Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Compound 6 (a)TLC of Piperidine Derivative With brucine

(b) TLC of Morpholine Derivative With brucine

Table-2, Separation of Mannich Bases by TLC using brucine Compound

Molecular Formula C13H19N3O2

Molecular Weight 249.30

Rf(1)

Rf(2)

N% Found 16.85

N% Calcd 16.82

1-[(4-hydroxyphenyl)(piperidin-10.18 0.54 yl)methyl]urea 1-[(4-hydroxyphenyl)(piperidin-1C13H19N3OS 265.37 0.12 0.56 15.83 15.80 yl)methyl]thiourea 1-[(4-hydroxyphenyl)(piperidin-1C13H20N4O 248.32 0.37 0.68 22.56 22.22 yl)methyl]guanidine 1-[(4-hydroxyphenyl)(morpholin-4C12H17N3O3 251.28 0.02 0.45 16.72 16.68 yl)methyl]urea 1-[(4-hydroxyphenyl)(morpholin-4C12H17N3O2S 267.34 0.30 0.56 15.72 15.71 yl)methyl]thiourea 1-[(4-hydroxyphenyl)(morpholin-4C12H18N4O2 250.29 0.23 0.50 22.38 22.30 yl)methyl]guanidine Mobile phase: (dichloromethane; 9.6: hexane; 0.6: formic acid; 0.6) Nitrogen content has been estimated by Kjeldahl method. Chiral separator brucine has been used to separate the enantiomers formed by racemic mixture. Each racemic mixture has two nitrogen atoms formed by urea (NH 2-CONH2), thiourea (NH2-CS-NH2) having two amino groups (NH2) and in guanidine (NH2-C=NH-NH2) having two amino groups (NH2) and one imino group (NH) and brucine has two tertiary nitrogen (N). Brucine is basic and thus have a tendency to crystallize with acids.

Histogram of Rf values by using brucine

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The acid-base reaction leaves the brucine protonated at the N(2) position. The formation of diastereomeric salts has been reported for thousands of organic compounds. Brucine: pKa: pK1 6.04, pK2 11.7. Phenolic –OH is present in each compound but the compound shows basic nature due to presence of nitrogen so all the compounds are precipitated in acidic medium because NH of piperidine (pKa=11.22)/morpholine (pKa=8.36) produce quarternization with OH of final compounds to show solubilization. 26-45 Table-3, Comparison of Rf values of racemic mixtures of Mannich bases and enantiomers separated by brucine Sr. No. Compound Rf Rf(1) Rf(2) 1 1-[(4-hydroxyphenyl)(piperidin-1-yl)methyl]urea 0.57 0.18 0.54 2 1-[(4-hydroxyphenyl)(piperidin-1-yl)methyl]thiourea 0.32 0.12 0.56 3 1-[(4-hydroxyphenyl)(piperidin-1-yl)methyl]guanidine 0.42 0.37 0.68 4 1-[(4-hydroxyphenyl)(morpholin-4-yl)methyl]urea 0.42 0.02 0.45 5 1-[(4-hydroxyphenyl)(morpholin-4-yl)methyl]thiourea 0.36 0.30 0.56 6 1-[(4-hydroxyphenyl)(morpholin-4-yl)methyl]guanidine 0.46 0.23 0.50

Histogram of Rf value comparison Method for Column Chromatography The column chromatography has been performed for the (1-[(4-hydroxyphenyl) (morpholin-4-yl) methyl] urea) in the glass column. The racemic compound has been dissolved in the mobile phase (dichloromethane; 9.6: hexane; 0.6: formic acid; 0.6) along with the brucine to make distereomer. Then the column has been packed with the Silica gel for TLC with cotton plug fitted at top & bottom of the column. Then the column is first washed with mobile phase to remove all soluble impurities and air bubbles, Then the mobile phase is loaded with solution of the compound. Then the mobile phase is run from the top to bottom to elute & separate the two distereomeric compond & the aliqoutes are collected a the 20mL interval. Finally the aliqoutes are analysed by the UV/Visible spectrometry.

Band of Compound 2

Band of Compound 1

(c) Column Chromatogrphy Of Disteromer Which shows 2 different Bands

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Nadim M. R. Chhipa et al. / International Journal of Advances in Pharmaceutical Research Table-4, Chiral separation data as per column chromatography (1-[(4-hydroxyphenyl) (morpholin-4-yl) methyl] urea) Sample No. λmax Absorbance Sample No. λmax Absorbance 1 0 0 14 266 3.474 2 0 0 15 266 3.835 3 0 0 16 266 3.925 4 266 1.038 17 266 2.078 5 266 1.140 18 266 1.550 6 266 1.289 19 266 0.287 7 266 1.352 20 241 1.255 8 266 1.558 21 241 1.423 9 266 1.920 22 241 2.231 10 266 2.565 23 241 2.102 11 266 2.875 24 241 1.372 12 266 3.089 25 241 0.318 13 266 3.280 Solvent: Methanol for final analysis The aliquots which show λmax at 266nm is regard as aliquots of Compound-1 & which shows λmax at 241nm regard as aliquots of Compound-2.

(a)

(b) Histogram (a) Absorbance of Compound-1 at 266nm (b) Absorbance of Compound-2 at 241nm

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Nadim M. R. Chhipa et al. / International Journal of Advances in Pharmaceutical Research Table-5, Final Analysis of Column aliquots after treatment with HCl Separated Compound λmax Absorbance 1 283 3.482 2 283 3.583

(a)

(b) Histogram (a) Final Analysis of Column aliquots after treatment with HCl at 283nm (b) Chiral Separation Data as per TLC after treatment with HCl (Morpholine-Guanidine Derivatives) at 274nm. Table-6, Chiral Separation Data as per TLC after treatment with HCl (1-[(4-hydroxyphenyl)(morpholin-4yl)methyl]guanidine) Band λmax Absorbance Upper 274 3.799 Lower 274 0.520 CONCLUSION The enantiomers produced by the chiral synthesis of Mannich bases of 4-hydroxy benzaldehyde with urea/thiourea/guanidine and piperidine/morpholine produced 3+3 sets of total 6 pairs of enantiomers having one chiral carbon. All the 6 derivatives are isoster of piperidine and morpholine in which CH2

(methylene) of piperidine is isoster of O (oxygen) of morpholine. The compounds are acidic in nature due to the presence of phenolic group (-OH) so brucine has been used as a separator moiety to resolute the R and S isomers produce in racemic mixture.). All the compounds have been characterized by UV, IR and specific rotation and TLC. Log P values of the

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Nadim M. R. Chhipa et al. / International Journal of Advances in Pharmaceutical Research compounds are found as follows due to the presence of variable electronegativity of O for urea (3.44), S for thiourea (2.58) and NH for guanidine (3.04+2.20=5.24): SCompound-4>Compound-6 (min) Compound-2: piperidine+thiourea, Compound-1: piperidine+urea, Compound-3: piperidine+guanidine, Compound-5: morpholine+thiourea, Compound-4: morpholine+urea, Compound-6: morpholine+guanidine Fantastic results show that piperidine (CH2) moiety linked with thiourea/urea/guanidine is isosteres has higher logP than morpholine (O) because the CH2 group is isosteres with O but the CH2 group is much more non polar than O so the logP values of piperidine moiety is higher than morpholine series. Specific rotation of the synthesised compounds showed remarkable similarity in piperidine/morpholine in thiourea, piperidine/morpholine in urea, piperidine/morpholine in guanidine series. Rf values of all the racemic mixtures and enantiomers separated by brucine has been observed. Separated isomers showed as Rf(1) is lower than Rf(2) in brucine. REFERENCES 1. March J. Advanced Organic Chemistry: Reactions, mechanism and structure, 4th Edition, Wiley, New York, 1992, 1512. 2. Sokolov VI. Introduction to Theoretical Stereochemistry, Gordon and Breach Science Publishers, New York, 1991, 278. 3. Wehner GK. Methods of Surface Analysis, Annual Book of ASTM standards, Vol.03.06 Philadelphia: America Society for Testing and Materials, 1989, 789-798. 4. Berglund RA, Graham PB, R. S. Mille RS. Application of in-situ FT-IR in Pharmaceutical Process and R & D: Spectroscopy 1993; 8(8): 31. 5. Bhushan R, Gupta D. Solution of (+/-)- Ibuprofen Using (-)-Brucine as a Chiral Selector by Thin Layer Chromatography: International Journal of Biomedical Chromatography 2004; 18(10): 838-840. 6. Sajewicz M, Pitka R, Kowalska T. Chiral Separations of Ibuprofen and Propranolol by TLC. A Study of the Mechanism and Thermodynamics of Retention: International Journal of Liquid Chromatography & Related Technologies 2005; 28(16): 2499-2513. 7. Sakai K, Hirayama N, Tamura R. Novel Optical Resolution Technologies, Resolution of 3(methylamino)-1-(2-thienyl)propan-1-ol, A New Key Intermediate for Duloxetine, With (S)-Mandelic

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